Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
Vascular Immunology Group, Heart Research Institute, University of Sydney, Newtown, New South Wales, Australia.
Clin Exp Pharmacol Physiol. 2020 Jan;47(1):49-59. doi: 10.1111/1440-1681.13169. Epub 2019 Oct 7.
Placental growth factor (PlGF) is decreased in early gestation of pregnant women who subsequently develop pre-eclampsia. In this study, pre-emptive treatment with PlGF to prevent pre-eclampsia was evaluated in an in vivo rodent model of experimental pre-eclampsia (EPE) induced by TNF-α and in an in vitro model of human first-trimester trophoblast invasion. Pregnant C57/BL6 mice were treated with recombinant mouse placental growth factor-2 (rmPlGF-2) 100 μg/kg/day IP from gestational day (gd) 10. Animals had EPE induced by continuous TNF-α infusion on gd 13 and were subject to either continuous blood pressure monitoring by radiotelemetry throughout pregnancy or live placenta T -weighted magnetic resonance imaging (MRI) to demonstrate placental function on gd 17. There was no difference in BP (P > .99), proteinuria (P = .9) or T values on MRI (P = .9) between control and rmPlGF-2-treated animals. On gd 13, animals treated with rmPlGF-2 demonstrated increased placenta PlGF (P = .01) and Toll-like receptor-3 (P = .03) mRNA expression as compared with controls. Fluorescent-labelled human uterine microvascular endothelial cells and HTR8/SVNeo cells were co-cultured on Matrigel and treated with recombinant human PlGF (rhPlGF) (10 ng/mL) and/or TNF-α (0.5 ng/mL). Trophoblast integration into endothelial networks was reduced by added TNF-α (P = .006), as was rhPlGF concentration in conditioned media (P < .0001). Cell integration was not ameliorated by addition of rhPlGF (P > .9). Although TNF-α-induced EPE was not reversed with pre-emptive rmPlGF-2, a further trial of pre-emptive rhPlGF in vivo is required to determine whether the absence of effect of rhPlGF demonstrated in vitro precludes PlGF as a preventative therapy for pre-eclampsia.
胎盘生长因子（PlGF）在随后发生子痫前期的孕妇的早孕中减少。在这项研究中，通过 TNF-α 诱导的实验性子痫前期（EPE）的体内啮齿动物模型和人早孕滋养细胞侵袭的体外模型评估了 PlGF 的预防性治疗以预防子痫前期。从妊娠第 10 天（gd）开始，用重组小鼠胎盘生长因子-2（rmPlGF-2）100μg/kg/天经腹腔内（IP）给予怀孕的 C57/BL6 小鼠。第 13 天 gd 时，动物接受连续 TNF-α 输注以诱导 EPE，并通过无线电遥测术进行连续血压监测，或进行胎盘 T-加权磁共振成像（MRI）以在 gd 17 时显示胎盘功能。对照组和 rmPlGF-2 处理组之间的 BP（P>.99）、蛋白尿（P=.9）或 MRI 上的 T 值（P=.9）没有差异。在 gd 13 时，与对照组相比，用 rmPlGF-2 处理的动物表现出胎盘 PlGF（P=0.01）和 Toll 样受体-3（P=0.03）mRNA 表达增加。用荧光标记的人子宫微血管内皮细胞和 HTR8/SVNeo 细胞在 Matrigel 上共培养，并用重组人 PlGF（rhPlGF）（10ng/mL）和/或 TNF-α（0.5ng/mL）处理。添加 TNF-α（P=0.006）减少了滋养细胞整合到内皮网络中，条件培养基中 rhPlGF 的浓度（P<.0001）也降低了。添加 rhPlGF 不能改善细胞整合（P>.9）。尽管用预先给予的 rmPlGF-2 不能逆转 TNF-α 诱导的 EPE，但需要在体内进一步进行预先给予 rhPlGF 的试验，以确定在体外证明 rhPlGF 无效是否排除 PlGF 作为子痫前期的预防治疗。
